Arrhythmia is classified into brady arrhythmia and tachy arrhythmia. Tachy arrhythmia is further classified into atrial arrhythmia and ventricular arrhythmia depending on a site of onset. Atrial tachy arrhythmia includes atrial fibrillation, atrial flutter, supraventricular tachycardia, and atrial extrasystole. Ventricular tachy arrhythmia includes ventricular fibrillation, ventricular flutter, ventricular tachycardia, and ventricular extrasystole.
Anti-arrhythmic agents have been used for treatment and prophylaxis of those tachy arrhythmias.
Currently, for classification of anti-arrhythmic agents, Vaughan Williams classification or Sicilian Gambit classification in which anti-arrhythmic agents are classified based on their receptors or target molecules is used.
Class I agents in the Vaughan-Williams classification correspond to Na channel blockers, which decrease the maximum rate of rise of action potential. Class I agents are further divided into three subgroups, i.e., Class Ia agents which can extend action potential duration and include quinidine, procainamide, and disopyramide, Class Ib agents which can shorten action potential duration and include lidocaine, and Class Ic agents which are Na channel blockers to extend refractory period by decreasing the maximum rate of rise of action potential and that include flecainide, propafenone, and pilsicainide. Class II agents area blockers. Class III agents are K+ channel blockers, and by inhibiting potential-dependent K+ channel, that lengthen the action potential duration and extend the effective refractory period. Examples of the K+ channel blocker include amiodarone, sotalol, and nifekalant. Class IV agents are Ca antagonists.
Among tachy arrhythmias, atrial fibrillation is representative arrhythmia which causes irregular systole of an atrium at 250 to 400 times per minute, or at even higher frequency. Atrial fibrillation is the greatest risk factor for causing heart failure and cardiogenic cerebral infarction, and converting atrial fibrillation to normal heart rhythms and preventing an occurrence of atrial fibrillation remain as an urgent and vital issue (see, Non Patent Document 1 and 2).
Atrial fibrillation is well known to occur based on high blood pressure, myocardial infarction, heart failure or the like as an underlying disorder. However, even without any organic heart disease, it may occur according to aging. The onset frequency starts to increase dramatically in people in their 60s, and it is known that the onset frequency is almost 10% in people over 80. In Japan, about 700,000 people fall ill every year, and number of patients who fall ill in Europe and USA is presumably 7,500,000.
As a therapeutic agent for atrial fibrillation, a pharmaceutical preparation selected from Class Ia, Class Ic, and Class III is used. However, the problem of those pharmaceutical preparations is that the atrial fibrillation stopping rate for getting back sinus rhythm from atrial fibrillation is as low as 30 to 40%. Furthermore, the pharmaceutical preparations selected from Class Ia and Class Ic decrease heart rate and blood pressure to deteriorate cardiac function. Furthermore, the pharmaceutical preparations selected from Class Ia, Class Ic, and Class III extend effective refractory period of ventricle and cause fatal arrhythmia such as Torsades de Pointes (ventricular tachycardia) or ventricular fibrillation. It was found according to a large-scale clinical trial CAST that, compared to a placebo, pharmaceutical preparations of Class Ic rather increase mortality in a patient with arrhythmia after myocardial infarction (see, Non Patent Document 3) and use of such pharmaceutical preparations is prohibited for arrhythmia of a patient with ischemic cardiac disease.
As described above, the action of lowering heart rate or blood pressure, inhibiting myocardial contraction or relaxation, or fatal proarrhythmic potential of anti-arrhythmic agents remains as a huge problem of drug therapy for atrial fibrillation.
An episode of atrial fibrillation restricts blood inflow from an atrium to a ventricle, and then yields a deterioration of cardiac function. As such, a heart failure is often caused. Furthermore, an episode of atrial fibrillation is often based on a heart failure as an underlying disorder and the therapeutic agent itself may cause a heart failure. Thus, application of drug therapy is very difficult for a patient with atrial fibrillation who shows lowered cardiac function. In particular, in case of a treatment of arrhythmia caused by atrial fibrillation, a pharmaceutical agent which shows a potent action on an atrium while not showing any effect on a ventricle is not developed yet. Thus, even if it is desired to solely extend the atrial effective refractory period, a ventricle is also affected so that the ventricular effective refractory period is also extended. For such reasons, a more potent therapeutic agent for arrhythmia caused by atrial fibrillation has a higher proarrhythmic potential like ventricular fibrillation as a side effect. Thus, a pharmaceutical agent which is useful for fixing atrial fibrillation to NSR (normal sinus rhythm) with a high selectivity and certainty while exhibiting no effect on cardiac function and having no proarrhythmic potential is not discovered at the present moment.
As prophylactic or therapeutic agents for atrial fibrillation or arrhythmia in atrial cells, diazepine compounds having an atrial selective K+ channel blocking action (see, Patent Document 1), 5-HT4 receptor antagonists (see, Patent Documents 2 and 3), p38 inhibitors (see, Patent Document 4), and pantenyl docosahexaenoate (see, Patent Document 5) are reported. Furthermore, the inventor of the present invention reported 4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine which has an inhibitory action on KD (kinetic cell death) of myocardium and is effective for myocardial necrosis or acute myocardial infarction without being accompanied by cardiodepressant effect (see, Patent Documents 6 and 7).
However, although all of those substances have been described to have an excellent anti-atrial fibrillation action like the effect of recovering normal sinus rhythm or lengthening atrial effective refractory period, there is no description about the suppression effect for proarrhythmic potential, which is a side effect of anti-arrhythmic agents.
There are many reports regarding 4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and a derivative thereof (see, Patent Documents 6 and 7). For example, it has been reported that the compound has an action of promoting the effect of carcinostatic agents (see, Patent Document 8) or an action of inhibiting the leak of Ca2+ from the sarcoplasmic reticulum by amelioration and/or stabilization of ryanodine receptor function (see, Patent Document 9), or the compound is useful as a muscle relaxation accelerator, a therapeutic agent for left ventricular diastolic dysfunction, a therapeutic agent for angina pectoris, a therapeutic agent for acute pulmonary edema, a blood ameliorant for microcirculation system, a therapeutic agent for hypertension, a therapeutic agent for ventricular tachycardia, and a therapeutic agent for Torsade de pointes (see, Patent Document 10).
It is recently found that 4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide (see, Patent Document 11), which has been developed by the inventor of the present invention, also is useful as a therapeutic or prophylactic agent for myocardium relaxation disorder that is observed in atrial arrhythmia as well as heart failure or high blood pressure, diastolic dysfunction, angina pectoris or myocardial infarction, hypertensive disease, or ischemic heart disease, heart failure, and ventricular arrhythmia. However, the selective action on atrial arrhythmia, in particular atrial fibrillation, is not confirmed. Instead, as a strong action on ventricle has been confirmed, it is expected that the proarrhythmic potential cannot be avoided when the compound is used for treatment of atrial fibrillation, for example.
As described above, the conventional pharmaceutical preparations suggested as therapeutic agents for atrial fibrillation or atrial arrhythmia, including 1,4-benzothiazepine-1-oxide derivative, have been found to have high effectiveness in terms of an anti-atrial fibrillation action. However, there are many cases in which the higher action on a ventricle is shown compared to the effectiveness for atrial fibrillation, and thus a problem occurs in that the proarrhythmic potential is negligible.
Under the circumstances, it is strongly desired to have a pharmaceutical preparation which enables recovery of atrial fibrillation to normal sinus rhythm and has no proarrhythmic potential.